In the United States, Japan, United Kingdom, and Sweden, birth defects affecting the growth and development of the genitourinary (GU) regions are becoming increasingly prevalent, with incidences ranging as high as 1 in 125 live births. To understand the basis for these malformations, scientists have begun to examine the function of developmental genes in GU tissues. At the forefront of these investigations are studies examining the role of the 5' HOX proteins during the formation of the GU region. In this report we discuss what is known about HOXA13 and HOXD13 function during GU development, highlighting some of the cellular and molecular mechanisms controlled by these proteins during the GU formation. Finally, the translational benefits of identifying HOX target genes are discussed; first to explain the prevalence of some GU defects as well as a mechanism to facilitate their prevention in the birth population.